文章：

整合素信号转接器：不仅仅是癌症故事中的形象

Integrin signalling adaptors: not only figurants in the cancer story

原文发布日期：2010-11-24

DOI: 10.1038/nrc2967

类型: Review Article

开放获取: 否

要点：

1. In cancer cells, integrin and growth factor receptor crosstalk leads to the recruitment of integrin signalling adaptors to assemble intracellular signalling platforms that result in cellular transformation and the control of migration and invasion. The biological effects that are regulated by integrin adaptors are dependent on their expression levels and on their phosphorylation status, which determine the association with binding effectors.
2. p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK, the integrin-linked kinase (ILK)–pinch–parvin (IPP) complex and p140 Cas-associated protein (p140CAP; also known as SRCIN1) integrin adaptors have a profound influence on all aspects of cancer progression, including initiation, progression and metastasis. Transgenic and xenograft animal models support the crucial role of these integrin adaptors in tumorigenesis.
3. In several human tumours, high expression of p130CAS, NEDD9, CRK, ILK, PINCH1 and PINCH2 correlates with increased disease progression, and the levels of parvin-β and p140CAP proteins are inversely correlated with malignancy. Current knowledge also implicates integrin adaptors in acquired resistance to cancer treatment.
4. In cancer cells, at the molecular level, these adaptors regulate signalling pathways that are required for the control of cell proliferation, survival and for actin cytoskeleton organization and extracellular matrix degradation. These events are fundamental for transformation and cancer progression, highlighting the integrin adaptors as key players in the onset of tumorigenesis.
5. Targeting integrin adaptors by modulating their expression levels or their activity in different types of cancer has been proven to be effective for interfering with malignancy, making the integrin adaptors suitable targets for cancer therapy.

要点翻译：

1. 在癌细胞中，整合素与生长因子受体的交互作用导致整合素信号适配子的募集，从而组装细胞内信号平台，最终引发细胞转化并调控迁移和侵袭能力。整合素适配子调控的生物学效应取决于其表达水平及磷酸化状态，这些因素决定了其与结合效应器的关联。
2. p130 Crk关联底物（p130CAS，亦称BCAR1）、神经前体细胞发育性下调表达蛋白9（NEDD9，亦称HEF1）、CRK、整合素连接激酶（ILK）-pinch-parvin（IPP）复合物以及p140 Cas关联蛋白（p140CAP，亦称SRCIN1）等整合素适配子对癌症进展的各个环节（包括发生、发展和转移）具有深远影响。转基因和异种移植动物模型证实了这些整合素适配子在肿瘤发生中的关键作用。
3. 在多种人类肿瘤中，p130CAS、NEDD9、CRK、ILK、PINCH1和PINCH2的高表达与疾病进展加速相关，而parvin-β和p140CAP蛋白水平则与恶性程度呈负相关。现有研究还表明整合素适配子与癌症治疗的获得性耐药相关。
4. 在分子层面，这些适配子通过调控信号通路来影响细胞增殖、存活、肌动蛋白细胞骨架组织以及细胞外基质降解。这些过程是细胞恶性转化和癌症进展的基础，凸显了整合素适配子在肿瘤发生起始阶段的关键作用。
5. 研究表明，通过调控整合素适配子在各类癌症中的表达水平或活性来靶向这些分子，能有效干预恶性肿瘤进程，这使整合素适配子成为癌症治疗的适宜靶标。

英文摘要：

Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects that are regulated by these adaptors in tumours might be crucial for the identification of new targets and the development of innovative therapeutic strategies for human cancer. In this Review we discuss the relevance of adaptor proteins in signalling that originates from integrin-mediated cell–extracellular matrix (ECM) adhesion and growth factor stimulation in the context of cell transformation and tumour progression. We specifically underline the contribution of p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK and the integrin-linked kinase (ILK)–pinch–parvin (IPP) complex to cancer, along with the more recently identified p140 Cas-associated protein (p140CAP; also known as SRCIN1).

摘要翻译： 

当前证据凸显，衔接（或支架）蛋白能够构建信号平台，在整合素依赖性黏附及生长因子受体激活的驱动下引发细胞转化。深入理解这些衔接蛋白在肿瘤中所调控的生物学效应，可能对于发现新靶点、开发人类癌症创新治疗策略至关重要。本综述探讨了衔接蛋白在整合素介导的细胞-细胞外基质（ECM）黏附与生长因子刺激所启动的信号通路中的相关性，并将其置于细胞转化与肿瘤进展的背景下。我们特别强调了 p130 Crk 相关底物（p130CAS；又称 BCAR1）、神经前体细胞表达且发育下调的 9（NEDD9；又称 HEF1）、CRK，以及整合素连接激酶（ILK）-Pinch-Parvin（IPP）复合体对癌症的贡献，同时还包括近期发现的 p140 Cas 相关蛋白（p140CAP；又称 SRCIN1）。

原文链接：

Integrin signalling adaptors: not only figurants in the cancer story